Insomnia in Women: Menopause and Melatonin
Insomnia in Women: Menopause and Melatonin
Part II of a III-Part Series
By Susan T. Marcolina, MD, FACP, and Beth Rosenshein, BSEE. Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; Beth has her BA in Electrical Engineering; both report no financial relationships relevant to this field of study.
As reviewed in part i of this series, many important endogenous and exogenous factors adversely affect the quality of sleep for women after ovarian failure. In fact, the National Sleep Foundation reports that 61% of women complain of insomnia after ovarian failure.1 An important regulatory hormone, melatonin plays a central role in the circadian rhythm of the sleep wake cycle, and declines of this hormone with age diminish sleep quality. Understanding how levels of melatonin are affected by changes that occur in women after ovarian failure gives important insights into the mechanisms by which sleep quality and, hence, quality of life, can be improved.
Melatonin: The chemical signal for darkness and sleep
Melatonin (N-acetyl-5-methoxytryptamine) is produced in the pineal gland from the essential amino acid tryptophan. Intrapineal tryptophan is initially converted to serotonin, which subsequently is enzymatically modified into the regulatory hormone melatonin. Since it is both lipophilic and hydrophilic, it is freely diffusible through cells and is transported in the bloodstream bound to albumin. It has a short half-life, is hepatically metabolized, and is excreted in the urine primarily as 6-sulfatoxymelatonin. Morning levels of urinary 6-STM are highly correlative with peak plasma nocturnal melatonin levels. The circadian body cycles of temperature and sleep-wake entrained by the SCN is modulated, in part, by the effects of melatonin.2
In healthy adults, daytime melatonin levels are low, averaging approximately 10 ng/mL, whereas they peak at nighttime to average values of 60 ng/mL. Exposure to light at night suppresses melatonin production and prevents the normal drop in nighttime core body temperature. Melatonin secretion is responsible not only for the sleep/wake cycle but also for the circadian rhythmicity of core body temperature, which is higher during the daytime compared to nighttime levels in diurnally active subjects.3 This temperature-lowering effect of melatonin is important, and may have therapeutic implications for peri- and post-menopausal women because hot flushes, a common symptom of this life transition, are associated with a nighttime increase in core temperature.
Melatonin levels are not influenced by gender; although both its secretion, as well as the time during which nocturnal production is elevated, decrease with age. Although wide inter-individual variations exist, the pattern for a given individual is generally stable.4
Relationship Between Pituitary, Sex Steroid Hormones, Sleep, and Melatonin in Ovarian Failure
Radioisotopic studies identified melatonin receptors in the SCN, as well as the preoptic nucleus of the hypothalamus, the cerebral cortex, and the thalamus, which may mediate melatonin's hypnotic and thermoregulatory circadian patterns.5 Melatonin receptors have also been identified in non-neuronal tissues such as renal tubular cells, cerebral arteries, ovarian granulosa cells, uterine myometrium, testicular Leydig cells, and prostate epithelial cells, demonstrating melatonin's wide ranging effects upon the regulation of reproductive, neuroendocrine, cardiovascular, and endothelial function.6 These actions of melatonin, as well as its influences on the sleep-wake cycle and the thermoregulatory cycle are, however, modulated by the presence of gonadal steroid hormones.7 In aging women, certain actions of melatonin are reduced, such as melatonin-induced endothelial nitric oxide (NO) levels and the nocturnal hypothermic response. These effects have implications for the development of nocturnal blood pressure elevations and hot flashes, respectively, which adversely affect the health of women in midlife.
Vakkuri and colleagues noted that declines in melatonin levels precede the follicle stimulating hormone (FSH) increase that occurs as ovarian failure progresses. Women in the 40-44 year age group averaged a 41% decline in melatonin levels followed by an additional 35% decrease between the ages of 50-59 years.8 Interestingly, Haimov and colleagues noted a robust clinical relationship between the nocturnal melatonin levels and the quality of sleep experienced by elderly patients. Both free living and nursing home patients with insomnia showed significantly lower peak urinary levels of sulfatoxymelatonin and significantly lower sleep efficiencies (sleep duration as a percentage of total time in bed) compared to young, healthy men and elderly subjects without insomnia. By contrast, elderly subjects without insomnia did not have significantly different sulfatoxymelatonin levels compared to the young male controls.9
Compounds that Alter Melatonin Secretion
Since changes in melatonin secretion can impact circadian rhythmicity, sleep, and interactions with the H-P-G system, it is important to be aware of substances that influence its secretion and, hence, affect sleep quality. Table 1 lists common drugs that affect melatonin levels.
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As of March 2007, the FDA required black box warnings on several drugs commonly prescribed for insomnia, including benzodiazepines and nonbenzodiazepine sedative hypnotic, due to several allergic reactions and complex sleep-related driving behaviors. Such drugs also deplete endogenous melatonin levels, further compromising sleep quality.10
Nonpharmacologic Treatments of Insomnia
Poor sleep hygiene habits contribute to sleep fragmentation, disturbances in circadian rhythm, and problems initiating sleep. Some basic sleep preparatory practices, outlined in Table 2, can improve sleep onset and efficacy. Physicians should review these guidelines with patients to illuminate areas that might need change, and individualize applications of these practices according to patient needs.
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Behavioral therapies such as biofeedback and muscle relaxation techniques and hypnotherapy can be useful adjunctive therapies for patients with chronic insomnia, and can be incorporated effectively into a sleep routine. They do, however, require special training and equipment not available or appropriate for all patients. Use of hypnotherapy in breast cancer patients for 4 one-hour/week sessions significantly improved both hot flashes and sleep quality.11 Meditation can be helpful and most individuals can easily learn the appropriate techniques.12 CBT is a powerful tool to correct patient misconceptions regarding sleep. Edinger and colleagues found that half of the 20 participants in a single-blinded short two-session CBT study experienced a 50% reduction in sleep fragmentation.13
References
1. National Sleep Foundation: Understanding Menopause. Available at: http://www.sleepfoundation.org/site/c.huIXKjMOIxF/b.2419231/k.63B3/understandingmenopause.htm Accessed on May 8, 2008.
2. Lang U, et al. Radioimmunological determination of urinary melatonin in humans: correlations with plasma levels and typical 24-hour rhythmicity. J Clin Endocrinol Metab. 1981;53:645-650.
3. Cagnacci A, et al. Melatonin: a major regulator of the circadian rhythm of core temperature in humans. J Clin Endocrinol Metab. 1992;75:447-452.
4. Waldhauser F, et al. Clinical aspects of the melatonin action: impact of development, aging, puberty, involvement of melatonin in psychiatric disease and importance of neuroendocrine interactions. Experientia. 1993;49:671-681.
5. Reppert SM, et al. Melatonin receptors step into the light: cloning and classification of subtypes. Trends Pharmacol Sci. 1996;17:100-102.
6. Zimmerman RC, Olcese JM. Melatonin. In: Medical Treatment of the Postmenopausal Woman. Lobos RJ, ed Elsevier, Inc; 2007. Pages 829-835.
7. Cagnacci A, et al. Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy. Clin Endocrinol (Oxf). 2001;54:261-266.
8. Vakkuri O, et al. Decrease in melatonin precedes follicle-stimulating hormone increase during perimenopause. Eur J Endocrinol. 1996;135:188-192.
9. Haimov I, et al. Sleep disorders and melatonin rhythms in elderly people. BMJ. 1994;309:167.
10. The US Food and Drug Administration. FDA Requests Label Change for All Sleep Disorder Drug Products. Accessed at http://www.fda.gov/bbs/topics/NEWS/2007/NEW01587.html. Accessed March 18, 2008.
11. Younus J, et al. Mind control of menopause. Womens Health Issues. 2003;13:74-78.
12. Norris G. Inviting silence: universal principles of meditation. 1st edition. New York: BlueBridge; 2004.
13. Edinger JD, Sampson WS. A primary care "friendly" cognitive behavioral insomnia therapy. Sleep. 2003; 26:177-182.
14. Reiter R, Robinson J. Melatonin: your body's natural wonder drug. New York: Bantam Books; 1995. Pages 134-135, 181-191.
15. Morin CM, et al. Nonpharmacological treatment of late-life insomnia. J Psychosom Res. 1999;46: 103-116.
As reviewed in part i of this series, many important endogenous and exogenous factors adversely affect the quality of sleep for women after ovarian failure. In fact, the National Sleep Foundation reports that 61% of women complain of insomnia after ovarian failure.Subscribe Now for Access
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